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Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034

Oncogene volume 23, pages 5099–5104 (2004)Cite this article

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase that mediates cell stress signaling initiated by diverse stimuli, such as H2O2 and TNFα. Owing to its critical role in promoting apoptosis, ASK1 activity is highly controlled in cells. Phosphorylation of ASK1 at Thr-845 has been correlated with its activation, while phosphorylation at Ser-967 negatively controls its death promoting activity. Here, we report the identification of a novel phosphorylation site at Ser-1034 in the C-terminal regulatory domain of ASK1. Mutating Ser-1034 to an unphosphorylatable Ala led to increased catalytic activity of ASK1 and enhanced proapoptotic function of ASK1. Thus, the proapoptotic function of ASK1 is suppressed in part by phosphorylation at its C-terminal regulatory domain, which may couple upstream survival kinases to the death regulatory machinery.

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Abbreviations

ASK1:

Apoptosis signal-regulating kinase 1

HA:

hemagglutinin

IP:

immunoprecipitate

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

MAPK:

mitogen-activated protein kinase

PMSF:

phenylmethylsulfonyl fluoride

TNF:

tumor necrosis factor

TRAF:

TNF receptor-associated factor

WT:

wild type

DAPI:

4′,6-diamidino-2-phenylindole

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Acknowledgements

We thank members of the Fu lab for helpful discussions, Lisa Montoya Cockrell for assistance in manuscript preparation, and Dr Bill Lane of Harvard Microchemistry facility for phosphopeptide sequence analysis. This work was supported in part by grants from American Heart Association (9950226N) and NIH/National Institute of General Medical Sciences (GM60033 and GM53165).

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Author notes

  1. Katsunori Fujii

    Present address: Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan

  2. Lixin Zhang

    Present address: SynerZ Pharmaceuticals, Inc., Lexington, MA, 02421, USA

  3. Jing Chen

    Present address: Howard Hughes Medical Institute, Harvard Institutes of Medicine, Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Katsunori Fujii, Hae Ryoun Park, Lixin Zhang & Haian Fu

  2. Graduate Program in Molecular and Systems Pharmacology, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Erinn Hoag Goldman

  3. Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Jing Chen

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  1. Katsunori Fujii
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Correspondence to Haian Fu.

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Fujii, K., Goldman, E., Park, H. et al. Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034. Oncogene 23, 5099–5104 (2004). https://doi.org/10.1038/sj.onc.1207668

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